2025
Chapter 49 Phase 0 & window of opportunity clinical trials
Reddy A, Bansal U, Lerner S. Chapter 49 Phase 0 & window of opportunity clinical trials. 2025, 249-253. DOI: 10.1016/b978-0-323-90186-4.00009-2.Peer-Reviewed Original ResearchExploratory investigational new drugClinical trialsPhase 1 clinical trialPreclinical animal studiesFood and Drug AdministrationInvestigational new drugOn-target effectsPhase 0 studiesDrug pharmacokineticsDrug efficacyDrug AdministrationAnimal studiesOncology drugsDrug trialsSuboptimal pharmacological propertiesNew drugsDrug approvalDrugDrug approval processCosts associated with drug developmentPharmacological propertiesDrug safetyTrialsDrug developmentTherapeutic areas
2024
Immunogenicity and Efficacy of Personalized Adjuvant mRNA Cancer Vaccines.
Berraondo P, Cuesta R, Sanmamed M, Melero I. Immunogenicity and Efficacy of Personalized Adjuvant mRNA Cancer Vaccines. Cancer Discovery 2024, 14: 2021-2024. PMID: 39485256, DOI: 10.1158/2159-8290.cd-24-1196.Peer-Reviewed Original ResearchPrognostic and predictive value of ultrasensitive ctDNA monitoring in a metastatic pan-cancer cohort treated with immune checkpoint inhibitors in the context of phase 1 clinical trials.
Toledo R, Calahorro García A, Mirallas O, Moreno A, Galvao V, Alonso G, Vieito M, Brana I, Oberoi A, Lostes-Bardaji M, Jimenez J, Sanz M, Viaplana C, Perez-Lopez R, Nuciforo P, Abbott C, Pugh J, Chen R, Boyle S, Garralda E. Prognostic and predictive value of ultrasensitive ctDNA monitoring in a metastatic pan-cancer cohort treated with immune checkpoint inhibitors in the context of phase 1 clinical trials. Journal Of Clinical Oncology 2024, 42: 2510-2510. DOI: 10.1200/jco.2024.42.16_suppl.2510.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsPhase 1 clinical trialMolecular residual diseaseCheckpoint inhibitorsCtDNA levelsICI responseDetection of molecular residual diseaseDynamics of circulating tumor DNATreated with immune checkpoint inhibitorsDuration of PFSRefractory metastatic tumorsImmune checkpoint inhibitionAccurate patient managementLiquid biopsy testingTreatment cycle 3Levels of ctDNAStage IV cancer patientsLiquid biopsy platformPan-cancer cohortAssociated with significant increasesSequencing of tumorsWhole-genome sequencing of tumoursCtDNA clearanceCtDNA dynamicsCtDNA monitoringA phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes
Bender C, Wiedeman A, Hu A, Ylescupidez A, Sietsema W, Herold K, Griffin K, Gitelman S, Long S, Gottlieb P, Strock R, Chesshir L, Redondo M, Williams C, Clements M, Moore W, DiMeglio L, Legge M, Mullen M, Sanchez J, Spall M, Woerner S, Gaglia J, Resnick B, Bryant N, Krishfield S, Turley J, Koshy N, Mackey M, Guttmann-Bauman I, Fitch R, Bartholow L, Shelso J, Al Nofal A, Hanisch K, Casas L, Thurlow B, Gottschalk M, Hashiguchi M, Paglia L, Lam A, Sanda S, Torok C, Wesch R, Moore D, Russell W, Smith T, Brown A, Brendle F, Haller M, Cintron M, Baidal D, Matheson D, Blaschke C, Moran A, Pappensus E, Leschyshyn J, Street A. A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes. Science Translational Medicine 2024, 16: eadn2404. PMID: 38718135, DOI: 10.1126/scitranslmed.adn2404.Peer-Reviewed Original ResearchConceptsRegulatory T cellsType 1 diabetesT cellsC-peptideFoxp3<sup>+</sup> regulatory T cellsNew-onset type 1 diabetesResidual B-cell functionPhase 1 clinical trialAutoimmune type 1 diabetesC-peptide preservationHigh-dose cohortPhase 2 randomized trialYears compared to placeboNew-onset T1DBaseline C-peptidePeripheral blood samplesSuppression in vitroDetected 1 weekMatching placeboAdoptive transferDouble-blindHigh-dosePrevent autoimmunityLow-doseFold expansionA pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease
van Dyck C, Mecca A, O’Dell R, Bartlett H, Diepenbrock N, Huang Y, Hamby M, Grundman M, Catalano S, Caggiano A, Carson R. A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease. Alzheimer's Research & Therapy 2024, 16: 20. PMID: 38273408, PMCID: PMC10809445, DOI: 10.1186/s13195-024-01382-2.Peer-Reviewed Original ResearchConceptsMild to moderate dementiaPositron emission tomographyAlzheimer's diseaseVolumetric MRIModerate dementiaClinical rating scalesSynaptic vesicle glycoprotein 2ACerebrospinal fluidMouse model of ADPharmacodynamic effectsPlacebo-controlled phase 1 clinical trialBiomarkers of AD pathologyClinical trialsCognitive measuresNominally significant differencesPhase 1 clinical trialModel of ADHippocampal cortexPhase 1/2 studyRating ScaleParallel-group trialSynaptic densityTrial registrationThe clinical trialPlacebo-controlledSigma-2 receptor ligands
2022
Genomic analysis and long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy
Kim IY, Mitrofanova A, Panja S, Sterling J, Srivastava A, Kim J, Kim S, Singer EA, Jang TL, Ghodoussipour S, Saraiya B, Mayer T, Sabaawy HE, Yuh B, Byun SS, Kim WJ, Horie S. Genomic analysis and long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy. Prostate International 2022, 10: 75-79. PMID: 35510081, PMCID: PMC9035380, DOI: 10.1016/j.prnil.2022.03.001.Peer-Reviewed Original ResearchCytoreductive radical prostatectomyPhase 1 clinical trialLong-term outcomesProstate cancerRadical prostatectomyOncologic outcomesSystemic therapyClinical trialsMulticenter phase 1 trialLong-term oncologic outcomesAndrogen deprivation therapyPrimary end pointEvidence of diseaseMajor complication rateCombination of surgeryMajor inclusion criteriaPhase 1 trialMetastatic prostate cancerB prostate cancerTumor necrosis factorLong-term useMinority of menDeprivation therapyM1 diseaseClavien-Dindo
2020
Practicalities of Setting Up a Phase I Clinical Trial Unit Within an Academic Center
Hong D, Marcelo-Lewis K, LoRusso P. Practicalities of Setting Up a Phase I Clinical Trial Unit Within an Academic Center. 2020, 71-83. DOI: 10.1007/978-3-030-47682-3_4.Peer-Reviewed Original Research
2016
A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer
Whitley M, Cardona D, Lazarides A, Spasojevic I, Ferrer J, Cahill J, Lee C, Snuderl M, Blazer D, Hwang E, Greenup R, Mosca P, Mito J, Cuneo K, Larrier N, O'Reilly E, Riedel R, Eward W, Strasfeld D, Fukumura D, Jain R, Lee W, Griffith L, Bawendi M, Kirsch D, Brigman B. A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Science Translational Medicine 2016, 8: 320ra4. PMID: 26738797, PMCID: PMC4794335, DOI: 10.1126/scitranslmed.aad0293.Peer-Reviewed Original ResearchConceptsSoft tissue sarcomasLocal recurrenceTumor bedClinical trialsIntravenous injectionPhase 1 clinical trialHuman phase 1 clinical trialCo-clinical studiesMicroscopic residual cancerPositive surgical marginsFuture clinical trialsCo-clinical trialsRates of reexcisionAdjuvant therapyResidual cancerSurgical marginsTreatment failureTissue sarcomasBreast cancerCommon causeIntraoperative detectionMouse modelPharmacokinetic profileSolid tumorsCancer
2015
Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target
Waters NJ, Daigle SR, Rehlaender BN, Basavapathruni A, Campbell CT, Jensen TB, Truitt BF, Olhava EJ, Pollock RM, Stickland KA, Dovletoglou A. Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target. Journal Of Controlled Release 2015, 220: 758-765. PMID: 26385168, DOI: 10.1016/j.jconrel.2015.09.023.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAnimalsAntineoplastic AgentsBenzimidazolesBiological AvailabilityChemistry, PharmaceuticalDelayed-Action PreparationsDNA MethylationDogsDrug Administration ScheduleDrug CarriersEnzyme InhibitorsEpigenesis, GeneticGene Expression Regulation, LeukemicHistone-Lysine N-MethyltransferaseHumansInfusions, IntravenousInjections, SubcutaneousLeukemia, Biphenotypic, AcuteMaleMethyltransferasesMiceRats, Sprague-DawleyTumor BurdenXenograft Model Antitumor AssaysConceptsXenograft modelRefractory acute leukemia patientsFurther evaluationPhase 1 clinical trialSubcutaneous bolus administrationAcute leukemia patientsTumor growth inhibitionDOT1L inhibitor pinometostatExtended-release formulationRat xenograft modelMLL-r leukemiaThrice dailyPharmacodynamic markersSC administrationBolus administrationClinical trialsSubcutaneous administrationComplete bioavailabilityDOT1L activityLeukemia patientsOral administrationPatient conveniencePreclinical studiesSmall molecule inhibitorsImproved exposure
2014
First Clinical Results of a Randomized Phase 2 Dose-Response Study of SGI-110, a Novel Subcutaneous (SC) Hypomethylating Agent (HMA), in 102 Patients with Intermediate (Int) or High Risk (HR) Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)
Garcia-Manero G, Ritchie E, Walsh K, Savona M, Kropf P, O’Connell C, Tibes R, Daver N, Jabbour E, Lunin S, Rosenblat T, Yee K, Stock W, Griffiths E, Mace J, Podoltsev N, Berdeja J, Issa J, Chung W, Naim S, Taverna P, Hao Y, Azab M, Kantarjian H, Roboz G. First Clinical Results of a Randomized Phase 2 Dose-Response Study of SGI-110, a Novel Subcutaneous (SC) Hypomethylating Agent (HMA), in 102 Patients with Intermediate (Int) or High Risk (HR) Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML). Blood 2014, 124: 529. DOI: 10.1182/blood.v124.21.529.529.Peer-Reviewed Original ResearchTreatment-naïve patientsMyelodysplastic syndromeChronic myelomonocytic leukemiaTreatment armsCMML patientsHypomethylating agentClinical responseAdverse eventsAstex PharmaceuticalsSGI-110Marrow CRNaïve patientsTransfusion independenceHematological improvementMDS patientsHigh-risk myelodysplastic syndromePhase 1 clinical trialECOG PS 2Treatment-naïve groupRisk myelodysplastic syndromesBaseline patient characteristicsFirst clinical resultsDose-response studySignificant differencesMedian followPredictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014, 515: 563-567. PMID: 25428504, PMCID: PMC4836193, DOI: 10.1038/nature14011.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedB7-H1 AntigenBiomarkersChemokine CX3CL1Clinical ProtocolsCTLA-4 AntigenDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticHumansImmunotherapyLymphocytes, Tumor-InfiltratingMaleMiddle AgedNeoplasmsTreatment OutcomeYoung AdultSelective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism
Zanin-Zhorov A, Weiss J, Nyuydzefe M, Chen W, Scher J, Mo R, Depoil D, Rao N, Liu B, Wei J, Lucas S, Koslow M, Roche M, Schueller O, Weiss S, Poyurovsky M, Tonra J, Hippen K, Dustin M, Blazar B, Liu C, Waksal S. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 16814-16819. PMID: 25385601, PMCID: PMC4250132, DOI: 10.1073/pnas.1414189111.Peer-Reviewed Original ResearchConceptsT cellsIL-17IL-21Forkhead box P3 (Foxp3) expressionRegulatory T cell subsetsPhase 1 clinical trialCollagen-induced arthritisIL-17 secretionRegulatory T cellsRheumatoid arthritis patientsTreatment of autoimmunityBox P3 expressionT cell subsetsDevelopment of autoimmunityROCK2 inhibitorIFN regulatory factor 4Healthy human subjectsT cell receptor stimulationIL-21 promoterSTAT3-dependent mechanismRegulatory factor 4Human T cellsArthritis patientsSiRNA-mediated inhibitionProinflammatory cytokinesBiodistribution and Radiation Dosimetry of LMI1195: First-in-Human Study of a Novel 18F-Labeled Tracer for Imaging Myocardial Innervation
Sinusas AJ, Lazewatsky J, Brunetti J, Heller G, Srivastava A, Liu YH, Sparks R, Puretskiy A, Lin SF, Crane P, Carson RE, Lee LV. Biodistribution and Radiation Dosimetry of LMI1195: First-in-Human Study of a Novel 18F-Labeled Tracer for Imaging Myocardial Innervation. Journal Of Nuclear Medicine 2014, 55: 1445-1451. PMID: 24994931, DOI: 10.2967/jnumed.114.140137.Peer-Reviewed Original ResearchConceptsAdministered activityBlood-pool standardized uptake valuesPhase 1 clinical trialCardiac nerve terminalsCardiac imagingMSv/MBqMean effective doseStandardized uptake valueRadiation doseOLINDA/EXMPatient radiation doseRadiation dose estimatesAdverse eventsBlood pressureWhole-body imagesClinical trialsBlood radioactivityMyocardial innervationNerve terminalsUrinary bladderHealthy subjectsLiver ratioHeart rateLung activityMyocardial uptake
2011
SU‐E‐T‐204: Real‐Time Monitoring of Age‐Related Macular Degeneration Radiosurgery Using Plastic Scintillation Dosimetry
Tien C, Cantley J, Hintenlang D, Bolch W, Firpo M, Chell E. SU‐E‐T‐204: Real‐Time Monitoring of Age‐Related Macular Degeneration Radiosurgery Using Plastic Scintillation Dosimetry. Medical Physics 2011, 38: 3533-3533. DOI: 10.1118/1.3612154.Peer-Reviewed Original ResearchAge-related macular degenerationTreatment of AMDPhase 1 clinical trialCadaver eye studiesInferior pars planaPre-clinical animal studiesExposure calibration factorsCalibration factorC-arm fluoroscopy unitEye StudyClinical trialsVision lossReal-time measurementMacular degenerationPars planaHigh doseAnimal studiesPlastic waveguidesTotal doseAge 65Real-time monitoringRetinal displacementDoseBlood vesselsMachine head
2009
Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor
Jimeno A, Hong D, Hecker S, Clement R, Kurzrock R, Pestano L, Hiscox A, Leos R, Kirkpatrick D, Eckhardt S, Herbst R. Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor. Journal Of Clinical Oncology 2009, 27: 3542-3542. DOI: 10.1200/jco.2009.27.15_suppl.3542.Peer-Reviewed Original ResearchPX-866Stable diseaseClinical trialsDay 1Drug-related severe adverse eventsMild side effect profilePhase 1 clinical trialStabilization of diseaseSevere adverse eventsDose-limiting toxicityPhase I trialSide effect profileAdvanced metastatic cancerP-mTOR levelsDose-dependent inhibitionLower drug dosesPhosphoinositide-3 kinase inhibitorPD endpointsExpansion cohortLast doseAbdominal discomfortAdverse eventsI trialEffect profileLoss of PTENRetrospective study of phase I clinical trials participation in patients at least 65 years of age at Karmanos Cancer Institute (KCI), Wayne State University, Detroit, Michigan
Vishnu P, Jasti P, Ding L, Heilbrun L, Venkatramanamoorthy R, LoRusso P, Heath E. Retrospective study of phase I clinical trials participation in patients at least 65 years of age at Karmanos Cancer Institute (KCI), Wayne State University, Detroit, Michigan. Journal Of Clinical Oncology 2009, 27: e20626-e20626. DOI: 10.1200/jco.2009.27.15_suppl.e20626.Peer-Reviewed Original ResearchKarmanos Cancer InstitutePhase 1 clinical trialOverall survivalClinical trialsPhase ICommon grade 3Median overall survivalPerformance status 1Retrospective chart reviewClinical trial participationYears of ageChart reviewElderly patientsElectrolyte abnormalitiesPatient agePatient demographicsPS 0Biologic agentsMedian ageStatus 1Lack of enrollmentRetrospective studyCombination therapyPatient subgroupsStudy criteria
2007
Barriers to phase I clinical trial protocol IRB approval at KCI
Wang D, Heath E, Powell A, Chaperon T, LaGrone F, LoRusso P. Barriers to phase I clinical trial protocol IRB approval at KCI. Journal Of Clinical Oncology 2007, 25: 9080-9080. DOI: 10.1200/jco.2007.25.18_suppl.9080.Peer-Reviewed Original ResearchInstitutional review boardClinical trialsIRB approvalMedian timePhase 1 clinical trialPhase 1 trialPhase 1 protocolPatient accrualAnti-cancer drug developmentStudy designProtocol approvalReview boardFinal approvalPhase IDrug development processSignificant financial relationshipTrialsApproval statusAverage timeHuman subjectsDrug developmentMolecular therapeuticsApprovalInitial review
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